tbuckley/cabot-search huggingface dataset:
Bioprinting of stem cell spheroids followed by post‐printing chondrogenic differentiation for cartilage tissue engineering
Authors: Monize Caiado Decarli, Adrián Seijas‐Gamardo, Francis L. C. Morgan, Paul Wieringa, Matthew B. Baker, Jorge Vicente L. Silva, Ângela Maria Moraes, Lorenzo Moroni, Carlos Mota
Journal: Advanced Healthcare Materials (2023)

Cartilage tissue presents low self-repair capability and lesions often undergo irreversible progression. Structures obtained by tissue engineering, such as those based in extrusion bioprinting of constructs loaded with stem cell spheroids may offer valuable alternatives for research and therapeutic purposes. Human mesenchymal stromal cell (hMSC) spheroids can be chondrogenically differentiated faster and more efficiently than single cells. This approach allows obtaining larger tissues in a rapid, controlled and reproducible way. However, it is challenging to control tissue architecture, construct stability, and cell viability during maturation. Herein, this work reports a reproducible bioprinting process followed by a successful post-bioprinting chondrogenic differentiation procedure using large quantities of hMSC spheroids encapsulated in a xanthan gum-alginate hydrogel. Multi-layered constructs are bioprinted, ionically crosslinked, and post chondrogenically differentiated for 28 days. The expression of glycosaminoglycan, collagen II and IV are observed. After 56 days in culture, the bioprinted constructs are still stable and show satisfactory cell metabolic activity with profuse extracellular matrix production. These results show a promising procedure to obtain 3D models for cartilage research and ultimately, an in vitro proof-of-concept of their potential use as stable chondral tissue implants.
Highlights from Recent Cancer Literature
Journal: Cancer Research (2023)

Breaking Insights| April 14 2023 Highlights from Recent Cancer Literature Author & Article Information Online ISSN: 1538-7445 Print ISSN: 0008-5472 ©2023 American Association for Cancer Research2023American Association for Cancer Research Cancer Res (2023) 83 (8): 1163–1164. https://doi.org/10.1158/0008-5472.CAN-83-8-BI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record April 14 2023 Citation Highlights from Recent Cancer Literature. Cancer Res 15 April 2023; 83 (8): 1163–1164. https://doi.org/10.1158/0008-5472.CAN-83-8-BI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search In contrast to other BRAFV600E mutant solid tumors, BRAFV600E mutant colorectal cancer has been difficult to target even with BRAF inhibitor combination therapy. Ruiz-Saenz and colleagues utilized a high-throughput kinase-activating mapping platform to identify targetable compensatory and resistance-mediating pathways after BRAF combination targeted therapy. They found the SRC kinase was induced after treatment and led to resistance through the β-catenin pathway in vitro and in vivo. Cotreatment with SRC inhibitors or upstream of SRC with COX2 inhibitors overcame resistance. Expert Commentary: The authors have identified a novel therapeutic strategy to improve response and to overcome resistance to BRAF inhibitor combinations in colorectal cancer. Ruiz-Saenz A, Atreya CE, Wang C, Pan B, Dreyer CA, Brunen D, et al. A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E colorectal tumors. Nat Cancer 2023;4:240–56. The NFIA-ETO2 fusion is exclusive to children with... You do not currently have access to this content.
Recent Advances in Nanoplatform Construction Strategy for Alleviating Tumor Hypoxia
Authors: Jing Shen, Guobo Chen, Linghao Zhao, Guoyang Huang, Hui Liu, Baolin Liu, Yuqing Miao, Yuhao Li
Journal: Advanced Healthcare Materials (2023)

Abstract Hypoxia is a typical feature of most solid tumors and has important effects on tumor cells' proliferation, invasion, and metastasis. This is the key factor that leads to poor efficacy of different kinds of therapy including chemotherapy, radiotherapy, photodynamic therapy, etc. In recent years, the construction of hypoxia‐relieving functional nanoplatforms through nanotechnology has become a new strategy to reverse the current situation of tumor microenvironment hypoxia and improve the effectiveness of tumor treatment. Here, the main strategies and recent progress in constructing nanoplatforms are focused on to directly carry oxygen, generate oxygen in situ, inhibit mitochondrial respiration, and enhance blood perfusion to alleviate tumor hypoxia. The advantages and disadvantages of these nanoplatforms are compared. Meanwhile, nanoplatforms based on organic and inorganic substances are also summarized and classified. Through the comprehensive overview, it is hoped that the summary of these nanoplatforms for alleviating hypoxia could provide new enlightenment and prospects for the construction of nanomaterials in this field.
Proinflammatory Macrophage Activation by the Polysialic Acid-Siglec-16 Axis Is Linked to Increased Survival of Patients with Glioblastoma
Authors: Hauke Thiesler, Lina Gretenkort, Leonie Hoffmeister, Iris Albers, Luisa Ohlmeier, Iris Röckle, Andrea Verhagen, Rouzbeh Banan, Nora Köpcke, Nicole Krönke, Friedrich Feuerhake, Felix Behling, Alonso Barrantes-Freer, Dorothee Mielke, Veit Rohde, Bujung Hong, Ajit Varki, Kerstin Schwabe, Joachim K. Krauss, Christine Stadelmann, Christian Hartmann, Herbert Hildebrandt
Journal: Clinical Cancer Research (2023)

Interactions with tumor-associated microglia and macrophages (TAM) are critical for glioblastoma progression. Polysialic acid (polySia) is a tumor-associated glycan, but its frequency of occurrence and its prognostic value in glioblastoma are disputed. Through interactions with the opposing immune receptors Siglec-11 and Siglec-16, polySia is implicated in the regulation of microglia and macrophage activity. However, due to a nonfunctional SIGLEC16P allele, SIGLEC16 penetrance is less than 40%. Here, we explored possible consequences of SIGLEC16 status and tumor cell-associated polySia on glioblastoma outcome.Formalin-fixed paraffin-embedded specimens of two independent cohorts with 70 and 100 patients with newly diagnosed glioblastoma were retrospectively analyzed for SIGLEC16 and polySia status in relation to overall survival. Inflammatory TAM activation was assessed in tumors, in heterotypic tumor spheroids consisting of polySia-positive glioblastoma cells and Siglec-16-positive or Siglec-16-negative macrophages, and by exposing Siglec-16-positive or Siglec-16-negative macrophages to glioblastoma cell-derived membrane fractions.Overall survival of SIGLEC16 carriers with polySia-positive tumors was increased. Consistent with proinflammatory Siglec-16 signaling, levels of TAM positive for the M2 marker CD163 were reduced, whereas the M1 marker CD74 and TNF expression were increased, and CD8+ T cells enhanced in SIGLEC16/polySia double-positive tumors. Correspondingly, TNF production was elevated in heterotypic spheroid cultures with Siglec-16-expressing macrophages. Furthermore, a higher, mainly M1-like cytokine release and activating immune signaling was observed in SIGLEC16-positive as compared with SIGLEC16-negative macrophages confronted with glioblastoma cell-derived membranes.Collectively, these results strongly suggest that proinflammatory TAM activation causes the better outcome in patients with glioblastoma with a functional polySia-Siglec-16 axis.
A New Frontier for Cancer Genetics: Identification of Germline–Somatic Associations
Authors: Siddhartha P. Kar
Journal: Cancer Research (2023)

Abstract Studies of the inherited or germline genome have identified rare mutations with large effects and common polymorphisms of more modest effect sizes that are associated with cancer risk. This research has substantially illuminated the etiology and development of cancer, with particular relevance to cancer prevention. In parallel, studies of the somatic or tumor genome have been instrumental in identifying the key drivers of cancer progression, significantly informing modern cancer therapy. While these studies have thus far largely been performed separately, integrative studies where the germline and somatic genomes are mapped in the same individuals have the potential to yield novel and holistic insights into cancer biology. In this issue of Cancer Research, Liu and colleagues report the results of integrative germline–somatic analyses in over 12,000 patients with cancer and 11 cancer types, identifying several associations where inherited variants that regulate the expression of a nearby gene in normal tissues are associated with tumor mutations in the same gene or with genome-wide somatic traits such as the tumor mutational burden. Although considerable follow-up work is required, the study is an important contribution to an emerging body of evidence that is demonstrating that the germline has a vital role in shaping the tumor genome. See related article by Liu et al., p. 1191
An <i>In Vivo</i> CRISPR Screen Identifies That SNRPC Promotes Triple-Negative Breast Cancer Progression
Authors: Xun-Xi Lu, Wen-Xiao Yang, Yu-Chen Pei, Hong Luo, Xiao-Guang Li, Yun-Jin Wang, Guo-Liang Zhang, Hong Ling, Zhi-Ming Shao, Xin Hu
Journal: Cancer Research (2023)

Dysregulation of RNA-binding proteins (RBP) is one of the characteristics of cancer. Investigating the biological functions and molecular mechanisms of abnormal RBPs can help uncover new cancer biomarkers and treatment strategies. To identify oncogenic RBPs in triple-negative breast cancer (TNBC), we employed an in vivo CRISPR screen and a TNBC progression model, which revealed small nuclear ribonucleoprotein polypeptide C (SNRPC), a subunit of the U1 small nuclear ribonucleoprotein particle (U1 snRNP), as a key modulator of TNBC progression. SNRPC was frequently upregulated, which corresponded to poor prognosis in patients with TNBC. SNRPC ablation significantly impaired the proliferation, migration, and invasion of TNBC cells in vitro and in vivo. In addition, SNRPC was essential for the stability of U1 snRNP and contributed to the RNA Pol II-controlled transcriptional program. Knockdown of SNRPC decreased RNA Pol II enrichment on a subset of oncogenes (TNFAIP2, E2F2, and CDK4) and reduced their expression levels. Furthermore, SNRPC deletion was confirmed to inhibit TNBC progression partially through regulation of the TNFAIP2-Rac1-β-catenin signaling pathway. Taken together, this data suggests that SNRPC plays an oncogenic role in TNBC, is a marker of poor prognosis, and may be a valuable therapeutic target for patients with intractable TNBC.A functional CRISPR screen identifies SNRPC as an RNA-binding protein that promotes the aggressiveness of breast cancer by facilitating Pol II-controlled transcription of oncogenes.
Combination Treatment with Sipuleucel-T and Abiraterone Acetate or Enzalutamide for Metastatic Castration-Resistant Prostate Cancer: STAMP and STRIDE Trials
Authors: Emmanuel S. Antonarakis, Sumit K. Subudhi, Christopher M. Pieczonka, Lawrence I. Karsh, David I. Quinn, Jason M. Hafron, Helen M. Wilfehrt, Matthew Harmon, Nadeem A. Sheikh, Neal D. Shore, Daniel P. Petrylak
Journal: Clinical Cancer Research (2023)

Abstract Purpose: We present long-term outcomes from 2 randomized studies [STAMP (with abiraterone, NCT01487863) and STRIDE (with enzalutamide, NCT01981122)] that were performed to study the impact of sequential or concurrent administration of androgen receptor–targeting agents (ARTAs) on sipuleucel-T immune response and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods: Sipuleucel-T was administered per current prescribing information. Results from STRIDE are presented together with updated STAMP results. Survival status of patients was updated using demographic information to query the National Death Index (NDI). Kaplan–Meier methodology was used to analyze survival. Results: Updated data reduced patient censoring in each study compared with the original analyses; the 95% confidence intervals (CIs) for OS are now estimable. Updated median OS (95% CI) is 33.3 (24.1–40.7) months for STAMP and 32.5 (26.0–45.1) months for STRIDE. There was no notable impact on median OS [HR, 0.727 (0.458–1.155); P = 0.177, reference = STRIDE]. OS with sequential administration was similar to concurrent administration [NDI update: HR, 0.963 (0.639–1.453); P = 0.845, reference = concurrent arm]. Sipuleucel-T potency, measured as antigen-presenting cell (APC) activation, was higher in subsequent infusions compared with the first infusion. Humoral responses (IgG + IgM antibody titers) to PA2024 and prostatic acid phosphatase were significantly elevated versus baseline. No new safety signals were observed. Conclusions: Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs.
Visual Investigation of Tumor‐Promoting Fibronectin Potentiated by Obesity in Pancreatic Ductal Adenocarcinoma Using an MR/NIRF Dual‐Modality Dendrimer Nanoprobe
Authors: Tingting Xu, Xiaoxuan Xu, Dongfang Liu, Di Chang, Siqi Li, Yeyao Sun, Jinbing Xie, Shenghong Ju
Journal: Advanced Healthcare Materials (2023)

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by dense stroma. Obesity is an important metabolic factor that greatly increases PDAC risk and mortality, worsens progression and leads to poor chemotherapeutic outcomes. With omics analysis, magnetic resonance and near-infrared fluorescence (MR/NIRF) dual-modality imaging and molecular functional verification, obesity as an important risk factor is proved to modulate the extracellular matrix (ECM) components and enhance Fibronectin (FN) infiltration in the PDAC stroma, that promotes tumor progression and worsens response to chemotherapy by reducing drug delivery. In the study, to visually evaluate FN in vivo and guide PDAC therapy, an FN-targeted nanoprobe, NP-CREKA, is synthesized by conjugating gadolinium chelates, NIR797 and fluorescein isothiocyanate to a polyamidoamine dendrimer functionalized with targeting peptides. A dual-modality strategy combining MR and NIRF imaging is applied, allowing effective visualization of FN in orthotopic PDAC with high spatial resolution, ideal sensitivity and excellent penetrability, especially in obese mice. In conclusion, the findings provide new insights into the potential of FN as an ideal target for therapeutic evaluation and improving treatment efficacy in PDAC, hopefully improving the specific management of PDAC in lean and obese hosts.
Intermittent fasting—the future treatment in NASH patients?
Authors: Iulia Minciuna, Suchira Gallage, Mathias Heikenwalder, Shira Zelber-Sagi, Jean-François Dufour
Journal: Hepatology (2023)

NASH is one of the leading causes of chronic liver disease with the potential of evolving towards end-stage liver disease and HCC, even in the absence of cirrhosis. Apart from becoming an increasingly prevalent indication for liver transplantation in cirrhotic and HCC patients, its burden on the healthcare system is also exerted by the increased number of noncirrhotic NASH patients. Intermittent fasting has recently gained more interest in the scientific community as a possible treatment approach for different components of metabolic syndrome. Basic science and clinical studies have shown that apart from inducing body weight loss, improving cardiometabolic parameters, namely blood pressure, cholesterol, and triglyceride levels; insulin and glucose metabolism; intermittent fasting can reduce inflammatory markers, endoplasmic reticulum stress, oxidative stress, autophagy, and endothelial dysfunction, as well as modulate gut microbiota. This review aims to further explore the main NASH pathogenetic metabolic drivers on which intermittent fasting can act upon and improve the prognosis of the disease, and summarize the current clinical evidence.
Redox dysregulation as a driver for DNA damage and its relationship to neurodegenerative diseases
Authors: Sina Shadfar, Sonam Parakh, Md Shafi Jamali, Julie D. Atkin
Journal: Translational Neurodegeneration (2023)

Abstract Redox homeostasis refers to the balance between the production of reactive oxygen species (ROS) as well as reactive nitrogen species (RNS), and their elimination by antioxidants. It is linked to all important cellular activities and oxidative stress is a result of imbalance between pro-oxidants and antioxidant species. Oxidative stress perturbs many cellular activities, including processes that maintain the integrity of DNA. Nucleic acids are highly reactive and therefore particularly susceptible to damage. The DNA damage response detects and repairs these DNA lesions. Efficient DNA repair processes are therefore essential for maintaining cellular viability, but they decline considerably during aging. DNA damage and deficiencies in DNA repair are increasingly described in age-related neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease. Furthermore, oxidative stress has long been associated with these conditions. Moreover, both redox dysregulation and DNA damage increase significantly during aging, which is the biggest risk factor for neurodegenerative diseases. However, the links between redox dysfunction and DNA damage, and their joint contributions to pathophysiology in these conditions, are only just emerging. This review will discuss these associations and address the increasing evidence for redox dysregulation as an important and major source of DNA damage in neurodegenerative disorders. Understanding these connections may facilitate a better understanding of disease mechanisms, and ultimately lead to the design of better therapeutic strategies based on preventing both redox dysregulation and DNA damage.
Caffeine Supplementation and FOXM1 Inhibition Enhance the Antitumor Effect of Statins in Neuroblastoma
Authors: Gia-Buu Tran, Jane Ding, Bingwei Ye, Mengling Liu, Yajie Yu, Yunhong Zha, Zheng Dong, Kebin Liu, Sunil Sudarshan, Han-Fei Ding
Journal: Cancer Research (2023)

Abstract High-risk neuroblastoma exhibits transcriptional activation of the mevalonate pathway that produces cholesterol and nonsterol isoprenoids. A better understanding of how this metabolic reprogramming contributes to neuroblastoma development could help identify potential prevention and treatment strategies. Here, we report that both the cholesterol and nonsterol geranylgeranyl-pyrophosphate branches of the mevalonate pathway are critical to sustain neuroblastoma cell growth. Blocking the mevalonate pathway by simvastatin, a cholesterol-lowering drug, impeded neuroblastoma growth in neuroblastoma cell line xenograft, patient-derived xenograft (PDX), and TH-MYCN transgenic mouse models. Transcriptional profiling revealed that the mevalonate pathway was required to maintain the FOXM1-mediated transcriptional program that drives mitosis. High FOXM1 expression contributed to statin resistance and led to a therapeutic vulnerability to the combination of simvastatin and FOXM1 inhibition. Furthermore, caffeine synergized with simvastatin to inhibit the growth of neuroblastoma cells and PDX tumors by blocking statin-induced feedback activation of the mevalonate pathway. This function of caffeine depended on its activity as an adenosine receptor antagonist, and the A2A adenosine receptor antagonist istradefylline, an add-on drug for Parkinson's disease, could recapitulate the synergistic effect of caffeine with simvastatin. This study reveals that the FOXM1-mediated mitotic program is a molecular statin target in cancer and identifies classes of agents for maximizing the therapeutic efficacy of statins, with implications for treatment of high-risk neuroblastoma. Significance: Caffeine treatment and FOXM1 inhibition can both enhance the antitumor effect of statins by blocking the molecular and metabolic processes that confer statin resistance, indicating potential combination therapeutic strategies for neuroblastoma. See related commentary by Stouth et al., p. 2091
Preclinical validation of a novel therapeutic strategy for choroid plexus carcinoma
Authors: Brice Martin, Tyler Garman, Madeline Laramee, Amy Wang, Xiaohu Zhang, Erin Beck, Kelli Wilson, Carleen Klumpp-Thomas, Crystal McKnight, Xin Xu, Natalie Hagen, David Holland, Nadia Dahmane, Craig J. Thomas, Mark Souweidane
Journal: Journal of Controlled Release (2023)
Delay in loop ileostomy reversal surgery does not impact upon post-operative clinical outcomes. Complications are associated with an increased loss of microflora in the defunctioned intestine
Authors: Emma L. Beamish, Judith Johnson, Barbara Shih, Rebecca Killick, Frank Dondelinger, Ciarra McGoran, Caitlan Brewster-Craig, Albert Davies, Arnab Bhowmick, Rachael J. Rigby
Journal: Gut Microbes (2023)

Loop ileostomy is a common surgical procedure to allow downstream tissue healing, with the aim of re-joining the bowel approximately 12 months later. The reversal procedure is associated with a substantial morbidity up to 40%. Our previous research demonstrated that defunctioned ileum becomes atrophied, with extensive microbial dysbiosis. This study sought to investigate the potential influence of delaying ileostomy reversal surgery upon both clinical and pathological outcomes. Post-operative clinical data was recorded, including routine blood test results, duration of hospital stay, length of time with stoma and incidence of post-operative complications. We measured ileal fibrosis and atrophy and assessed whether these, or dysbiosis, were impacted by the length of time a stoma was in place, or were linked to clinical outcomes. Associations between clinical data were investigated using scatterplot matrix analysis and t-tests. We found no differences in time between ileostomy formation and reversal in patients experiencing complications vs. individuals with no complications. Furthermore, there were no correlations between days with stoma and pathological measures, such as atrophy or fibrosis, and no ongoing increases in collagen production at the time of reversal surgery. This data suggests that the length of time a stoma is in place does not impact on the likelihood of complications. The incidence of complications is associated with increased loss of microbiota in the defunctioned ileum, but importantly, the decrease in bacteria is not linked to time with stoma. Microbiota diversity in the functional and defunctioned limb correlated within an individual, and was not significantly different between those who experienced complications following surgery vs. those that didn't. Microbiota diversity was also not significantly impacted through delay (>365 days) in stoma reversal. We propose that methods to restore intestinal microbiota numbers, and not necessarily their composition, prior to reversal should be explored to improve the clinical outcomes of ileostomy reversal surgery.
Inside Information: Black Carbon Exposure and the Early-Childhood Gut Microbiome
Authors: Silke Schmidt
Journal: Environmental Health Perspectives (2023)

Vol. 131, No. 4 Science SelectionOpen AccessInside Information: Black Carbon Exposure and the Early-Childhood Gut Microbiomeis accompanied byAccumulation of Black Carbon Particles in Placenta, Cord Blood, and Childhood Urine in Association with the Intestinal Microbiome Diversity and Composition in Four- to Six-Year-Old Children in the ENVIRONAGE Birth Cohort Silke Schmidt Silke Schmidt Search for more papers by this author